Project Summary/Abstract The impact of the obesity epidemic in the US has been estimated to endanger the health of up to 30% of Americans by increasing the risk of diabetes, hypertension, stroke, and cancer as well as leading to 300,000 deaths annually. In order to lessen the negative impact of obesity, there is a need to better understand the neurobiology of feeding and metabolism in a manner that could contribute to the development of effective therapeutics. Attempts to understand the neural basis of feeding and metabolism often involve the study of individual neuropeptides that alter caloric intake and/or energy expenditure. Anatomical studies have implicated subregions of the hypothalamus as sites of action for several dozen peptide regulators of feeding behavior and body weight. Specifically, the ventromedial nuclei of the hypothalamus (VMN) exert powerful control over feeding and metabolism through a broad array of both central and peripheral signaling molecules. For example, leptin, a well- studied peripheral signal produces hypophagia when administered into the VMN. Centrally, the actions of the VMN on energy homeostasis are also dependent on the activity of neural inputs synthesized and released by other brain regions such as the neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP), which promotes energy expenditure and decreases feeding behavior. Thus, neurons in the VMN likely integrate both neural and peripheral signals in order to regulate energy homeostasis. Preliminary data in this proposal support the hypothesis that leptin and PACAP interact in the VMN by regulating shared intracellular signaling pathways that lead to hypophagia. This is not surprising given the common and parallel features between PACAP and leptin in terms of anatomy, behavioral and metabolic outcomes, gene activation patterns, and functional dependency. This proposal examines several points of convergence among the intracellular signals produced by leptin and PACAP including the JAK-STAT signaling cascade and BDNF expression. Moreover, PACAP and leptin are ideal candidates to study the functional interactions between a tonically peripheral signal and a synaptically released neuropeptide that together could alter the activity of a broad neural network responsible for feeding behavior and energy homeostasis. In the hypothalamic VMN, we will examine the intracellular signaling links between PACAP and leptin (aim 1), and the functional relationship between PACAP and leptin under chronic conditions of leptin receptor dysregulation with obesity, hyperleptinemia without obesity, and diet induced obesity (aim 2).